Assessment of Cancer Predisposition Syndromes in a National Cohort of Children With a Neoplasm.

Importance: To improve diagnostics of cancer predisposition syndromes (CPSs) in children with cancer, it is essential to evaluate the effect of CPS gene sequencing among all children with cancer and compare it with genetic testing based on clinical selection. However, a reliable comparison is difficult because recent reports on a phenotype-first approach in large, unselected childhood cancer cohorts are lacking. Objective: To describe a national children's cancer center's experience in diagnosing CPSs before introducing routine next-generation sequencing. Design, Setting, and Participants: This retrospective cohort study was conducted at the National Retinoblastoma Treatment Center (Amsterdam, the Netherlands) and the Princess Máxima Center for Pediatric Oncology (Utrecht, Netherlands) and included Dutch pediatric patients with a new diagnosis of neoplasm between June 1, 2018, and December 31, 2019. Follow-up was at least 18 months after neoplasm diagnosis. Data analysis was conducted from July 2021 to February 2022. Exposures: As part of routine diagnostics, pediatric oncologists and ophthalmologists checked for characteristics of CPSs and selected children for referral to clinical geneticists and genetic testing. Main Outcomes and Measures: Detected cancer predisposition syndromes. Results: A total of 824 patients (median [range] age at diagnosis 7.5 [0-18.9] years; 361 girls [44%]) were assessed, including 335 children with a hematological neoplasm (41%) and 489 (59%) with a solid tumor. In 71 of 824 children (8.6%), a CPS was identified, of which most (96%) were identified by a phenotype-driven approach. Down syndrome and neurofibromatosis type 1 were the most common CPSs diagnosed. In 42 of 71 patients (59%), a CPS was identified after these children developed a neoplasm. The specific type of neoplasm was the most frequent indicator for genetic testing, whereas family history played a minor role. Conclusions and Relevance: In this cohort study of children with a neoplasm, the prevalence of CPSs identified by a phenotype-driven approach was 8.6%. The diagnostic approach for identifying CPSs is currently shifting toward a genotype-first approach. Future studies are needed to determine the diagnostic value, as well as possible disadvantages of CPS gene sequencing among all children with cancer compared with the phenotype-driven approach.

Anxiety and depression in patients who receive anti-VEGF treatment and the usability and feasibility of e-mental health support: the E-PsEYE pilot study.

PURPOSE: E-PsEYE is an internet-based, guided self-help course, following the principles of cognitive behavioural therapy, to reduce anxiety and depression in patients with retinal exudative diseases who receive anti-vascular endothelial growth factor (anti-VEGF) treatment. The purpose of this study was to determine the prevalence and related factors of anxiety and depression in this population and evaluate the usability and feasibility of E-PsEYE. METHODS: Symptoms of anxiety and depression and related factors were determined in 90 patients (mean age 77 years, 58% female), based on multiple logistic regression analysis. Five patients with mild to moderate depression/anxiety tested the usability of E-PsEYE. They were asked to think aloud while completing two modules of the intervention and freely explore system features. The feasibility of the total E-PsEYE intervention was tested in 14 patients with mild to moderate depression/anxiety, based on a single arm pre-post study with a follow-up of three months: fidelity, acceptability, feasibility of study methods and potential effectiveness were explored. RESULTS: Fifty-three percent of the total study population experienced at least mild anxiety and/or depression symptoms. Especially female patients (odds ratio (OR) 3.89, 95% confidence interval (CI) 1.33-11.40), those who experienced limitations in daily life activities due to vision loss (OR 9.67; 95% CI 3.18-29.45) and those who experienced loneliness (OR 3.53, 95% CI 1.14-10.95) were more likely to have anxiety/depression. The usability study raised several possibilities for improvement, based on which E-PsEYE was improved. The feasibility study showed adequate fidelity and acceptability. Most participants were satisfied with the results (79%). There was a high response rate, no loss to follow-up and mental health problems decreased in more than half of the patients. The Wilcoxon signed rank test indicated lower post-test ranks compared to pre-test ranks (depression Z -1.34, p = 0.18; anxiety Z -1.45, p = 0.15). CONCLUSIONS: Mental health problems are prevalent in patients who receive anti-VEGF treatment. Healthcare providers should recognise these problems and related factors in order to refer patients to appropriate care in a timely manner. Outcomes on the usability and feasibility of E-PsEYE are promising as a prelude to performing a randomised controlled trial, which will shed more light on its (cost-)effectiveness.

At What Age Could Screening for Familial Retinoblastoma Be Discontinued? A Systematic Review.

The aim of this systematic review is to assess the latest age at diagnosis for detection of familial retinoblastoma in order to evaluate at what age screening of at-risk children could be discontinued. Extended screening beyond this age would result in unnecessary patient burden and costs. However, discontinuing screening prematurely would have the adverse effect of missing tumors. We performed a literature search (PubMed, Embase, CINAHL and the Cochrane Library) up until February of 2021 and systematically included studies where patients had a family history of retinoblastoma, a known age at diagnosis, and who were ophthalmologically screened for retinoblastoma from birth. A total of 176 familial retinoblastoma patients from 17 studies were included in this review. Based on 48 months of age being the latest age of diagnosis, ophthalmological screening for familial retinoblastoma could safely be discontinued at age four years.

Varicella zoster-associated acute retinal necrosis and central nervous system complications in natalizumab treated MS patients.

There is not much awareness of varicella zoster virus (VZV) associated central nervous system (CNS) infections under treatment with natalizumab. Here we describe two natalizumab treated MS patients who developed acute retinal necrosis combined with CNS vasculitis caused by VZV. In natalizumab treated patients, visual symptoms atypical of optic neuritis should be promptly evaluated by an ophthalmologist. Currently, a total of 12 cases of natalizumab-associated VZV CNS or retinal infections are reported in literature. Our two cases and overview of currently available data provide information on prognosis and treatment decisions of this rare but devastating complication.

Recommendations for Long-Term Follow-up of Adults with Heritable Retinoblastoma.

PURPOSE: To generate recommendations for long-term follow-up of adult survivors of heritable retinoblastoma. DESIGN: We convened a meeting of providers from retinoblastoma centers around the world to review the state of the science and to evaluate the published evidence. PARTICIPANTS: Retinoblastoma is a rare childhood cancer of the retina. Approximately 40% of retinoblastoma cases are heritable, resulting from a germline mutation in RB1. Dramatic improvements in treatment and supportive care have resulted in a growing adult survivor population. However, survivors of heritable retinoblastoma have a significantly increased risk of subsequent malignant neoplasms, particularly bone and soft tissue sarcomas, uterine leiomyosarcoma, melanomas, and radiotherapy-related central nervous system tumors, which are associated with excess morbidity and mortality. Despite these risks, no surveillance recommendations for this population currently are in place, and surveillance practices vary widely by center. METHODS: Following the Institute of Medicine procedure for clinical practice guideline development, a PubMed, EMBASE, and Web of Science search was performed, resulting in 139 articles; after abstract and full-text review, 37 articles underwent detailed data abstraction to quantify risk and evidence regarding surveillance, if available. During an in-person meeting, evidence was presented and discussed, resulting in consensus recommendations. MAIN OUTCOME MEASURES: Diagnosis and mortality from subsequent neoplasm. RESULTS: Although evidence for risk of subsequent neoplasm, especially sarcoma and melanoma, was significant, evidence supporting routine testing of asymptomatic survivors was not identified. Skin examination for melanoma and prompt evaluation of signs and symptoms of head and neck disease were determined to be prudent. CONCLUSIONS: This review of the literature confirmed some of the common second cancers in retinoblastoma survivors but found little evidence for a benefit from currently available surveillance for these malignancies. Future research should incorporate international partners, patients, and family members.

Full-width postlaminar optic nerve tumor invasion of retinoblastoma as risk-factor for leptomeningeal spread of retinoblastoma. A case report and review of the literature.

We present a 6-year-old boy with unilateral retinoblastoma of the left eye. MRI showed an intraocular tumor that extended into the optic nerve beyond the lamina cribrosa. The affected eye was enucleated and the optic nerve resection margin proved to be free. Following protocol, this patient received six courses of adjuvant systemic chemotherapy. Unfortunately, after 5 months this patient returned with the leptomeningeal spread of the tumor and died quickly thereafter.Histopathologic analysis of the enucleated eye and distal optic nerve revealed that the postlaminar tumor cells occupied the entire width of the optic nerve, extending all the way up to the pia mater, whereas, more often the tumor invasion is restricted to the center of the optic nerve. This was also visible on the MR images where contrast enhancement occupied the entire nerve width. A resection margin with tumor cells is recognized as a risk factor for metastasis, but perhaps the proximity of tumor cells to the leptomeninges should also be judged with caution as a potential increased risk for metastatic spread.

Optical coherence tomography (OCT) to image active and inactive retinoblastomas as well as retinomas.

PURPOSE: To illustrate Optical Coherence Tomography (OCT) images of active and inactive retinoblastoma (Rb) tumours. METHODS: Current observational study included patients diagnosed with retinoblastoma and retinoma who were presented at Amsterdam UMC and Jules-Gonin Eye Hospital, between November 2010 and October 2017. Patients aged between 0 and 4 years were imaged under general anaesthesia with handheld OCT in supine position. Patients older than 4 years were imaged with the conventional OCT (Heidelberg Engineering, Heidelberg Spectralis, Germany). All patients included were divided into two groups: active and inactive tumours (retinoma and regression patterns). Patients' medical records and OCT images were analysed during meetings via discussions by ophthalmologists and physicists. RESULTS: Twelve Dutch and 8 Swiss patients were divided into two groups: 2 patients with active tumour versus 18 patients with inactive tumour. Subsequently, inactive group could be divided in two groups, which consisted of 10 patients with retinoma and 8 patients with different regression pattern types. Of all included patients, 15 were male (75%). Median age at diagnosis was 18.0 months (range 0.19-715.2 months). A total of 12 retinoblastoma (active and inactive) and 8 retinoma foci were investigated by OCT. No distinction could be made between active and inactive tumours using only OCT. CONCLUSION: Optical coherence tomography alone cannot distinguish between active and inactive Rbs. However, handheld OCT adds useful information to the established imaging techniques in the monitoring and follow-up of retinoblastoma patients. With this study, we provide an overview of OCT images of active and inactive Rbs.

Phase-based OCT angiography in diagnostic imaging of pediatric retinoblastoma patients: abnormal blood vessels in post-treatment regression patterns.

Phase-based OCT angiography of retinoblastoma regression patterns with a novel handheld 1050 nm clinical imaging system is demonstrated for the first time in children between 0 and 4 years old under general anesthesia. Angiography is mapped at OCT resolution by flow detection at every pixel with en-face projection from the volume between nerve fiber layer and retinal pigment epithelium. We show a striking difference between blood vasculature of healthy retina, and retinoblastoma regression patterns after chemotherapy, as well as varying complexity of abnormal vasculature in regression patterns types 2, 3, and 4. We demonstrate abnormal, tortuous and prominent vasculature in type 3 regression patterns having the highest risk of tumor recurrences and a lower probability to reduction into flat scars. The ability to visualize 3-D angiography might offer new insights in understanding of retinoblastoma development and its response to therapy.

Cosmetic results of enucleation and/or external beam radiation therapy in 195 retinoblastoma survivors.

PURPOSE: To report the cosmetic outcome and late effects of enucleation and/or irradiation for retinoblastoma and to evaluate the role of orbital implants. METHODS: Patients (age >4 years) enucleated and/or irradiated for retinoblastoma, visiting the hospital for routine follow-up (April 2013 to May 2015), were included in our cross-sectional study. Data were obtained via clinical records, questionnaires, physical measurements and standardized photographs. Two independent observers scored the cosmetic features: upper eyelid position, lower eyelid position, volume deficiency, and prosthesis motility and overall cosmetic appearance. RESULTS: A total of 195 patients participated. Ptosis was seen in 45 (28.3%) patients, lower lid sagging in 45 (28.3%). Both complications were associated with the orbital implant; ptosis being more common with increasing implant size (5.6% without implant, 16.7% with small implant, 37.1% with medium implant and 76.9% with large implant) and lower lid sagging being more common in patients without implant (20% with implant versus 37.5% without). Volume loss of the superior sulcus was seen in 107 sockets (66.9%), most frequent in additionally irradiated patients (χ2 (2) = 42.7, p < 0.001) and in patients without implant (χ2 (2) = 11.92, p = 0.003). Prosthesis motility was better in patients with orbital implant, regardless of the size. CONCLUSION: Minor late and potentially treatable effects were seen in patients with implant. Larger sized implants were associated with a higher incidence of ptosis; implant size did not affect subjective outcome with respect to volume or prosthetic motility. Treatment with EBRT had a less favourable outcome.

Identification of proteins associated with clinical and pathological features of proliferative diabetic retinopathy in vitreous and fibrovascular membranes.

PURPOSE: To identify the protein profiles in vitreous associated with retinal fibrosis, angiogenesis, and neurite formation in epiretinal fibrovascular membranes (FVMs) in patients with proliferative diabetic retinopathy (PDR). METHODS: Vitreous samples of 5 non-diabetic control patients with vitreous debris and 7 patients with PDR membranes were screened for 507 preselected proteins using the semi-quantitative RayBio® L-series 507 antibody array. From this array, 60 proteins were selected for a custom quantitative antibody array (Raybiotech, Human Quantibody® array), analyzing 7 control patients, 8 PDR patients with FVMs, and 5 PDR patients without FVMs. Additionally, mRNA levels of proteins of interest were measured in 10 PDR membranes and 11 idiopathic membranes and in retinal tissues and cells to identify possible sources of protein production. RESULTS: Of the 507 proteins screened, 21 were found to be significantly elevated in PDR patients, including neurogenic and angiogenic factors such as neuregulin 1 (NRG1), nerve growth factor receptor (NGFR), placental growth factor (PlGF) and platelet derived growth factor (PDGF). Angiopoietin-2 (Ang2) concentrations were strongly correlated to the degree of fibrosis and the presence of FVMs in patients with PDR. Protein correlation analysis showed PDGF to be extensively co-regulated with other proteins, including thrombospondin-1 and Ang2. mRNA levels of glial-derived and brain/derived neurotrophic factor (GDNF and BDNF) were elevated in PDR membranes. These results were validated in a second study of 52 vitreous samples of 32 PDR patients and 20 control patients. CONCLUSIONS: This exploratory study reveals protein networks that potentially contribute to neurite outgrowth, angiogenesis and fibrosis in the formation of fibrovascular membranes in PDR. We identified a possible role of Ang2 in fibrosis and the formation of FVMs, and of the neurotrophic factors NRG1, PDGF and GDNF in neurite growth that occurs in all FVMs in PDR.

Economic evaluation of an e-mental health intervention for patients with retinal exudative diseases who receive intraocular anti-VEGF injections (E-PsEYE): protocol for a randomised controlled trial.

INTRODUCTION: Because of the great potential of vascular endothelial growth factor inhibitors (anti-VEGF) for retinal exudative diseases, an increased number of patients receives this treatment. However, during this treatment, patients are subjected to frequent invasive intravitreal injections, and the effects on reversing the process of vision loss are uncertain, which may have negative consequences for patients' mental health. One in three patients experience at least mild symptoms of depression/anxiety. To support patients in dealing with these symptoms, an e-mental health intervention (called E-PsEYE) has been developed. E-PsEYE is based on cognitive-behavioural therapy (CBT) and contains nine modules. A stepped-care model with three steps will be used to deliver the intervention: (1) providing information and psychoeducation, (2) when symptoms of depression/anxiety persist, guided CBT is offered and supported by social workers from low vision rehabilitation services and (3) when symptoms still persist, patients are referred to their general practitioner. METHODS AND ANALYSIS: An economic evaluation from a healthcare and societal perspective will be conducted alongside a multicentre randomised controlled trial in two parallel groups to evaluate whether E-PsEYE is cost-effective in comparison with usual care. Participants (n=174) will be 50 years or older, have retinal exudative diseases, receive anti-VEGF treatment and have mild symptoms of depression/anxiety (assessed prior to randomisation). Main outcome measures are: depression (Patient Health Questionnaire-9), anxiety (Hospital Anxiety and Depression Scale-Anxiety) and quality-adjusted life-years (determined with the Health Utility Index-3 and the EuroQol-5 dimensions). Five measurements take place: at baseline and after 3, 6, 9 and 12 months. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee of the VU University Medical Centre Amsterdam. It will provide new and essential information on the cost-effectiveness of an innovative intervention for a vulnerable population. Outcomes will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION: http://www.trialregister.nl, identifier: NTR6337.

Feasibility of RetinoQuest: e-health application to facilitate and improve additional care for retinoblastoma survivors.

PURPOSE: The current study aimed to evaluate the feasibility of RetinoQuest in clinical practice, from survivors and healthcare professionals' (HCPs) point of view. METHODS: RetinoQuest is a touch screen computer program to monitor health-related quality of life (HRQoL) of retinoblastoma survivors via patient-reported outcome measures (PROMs) targeting children (4-10 years) as evaluated by their parents (proxy measures), adolescents (11-18 years), and adults. Feasibility was evaluated by the actual time taken to complete the PROMs, acceptability of the time as perceived by the users, the content of PROMs in RetinoQuest, and overall satisfaction with RetinoQuest. RESULTS: Ninety-six survivors participated: 41 parents of children, 38 adolescents, and 17 adults. Mean time to complete the evaluation form was 7.8 min (median 6.7, range 2.4-24.5), and 90% of the users stated that the time needed to complete PROMs in RetinoQuest was acceptable. The majority of users reported that it was important to answer the questions (88% of the parents, 66% of the adolescents, and 76% of the adult survivors) and that all important issues were covered, e.g., no missing questions (78, 84, and 76%, respectively). Satisfaction rate was high, 7.8 according to parents, 8.1 according to adolescents, and 7.7 for adults. CONCLUSIONS: RetinoQuest is a feasible e-health application to monitor HRQoL in retinoblastoma survivors in clinical practice. IMPLICATIONS FOR CANCER SURVIVORS: This tool allows for open and structured communication which can lead to early detection of psychosocial impacts on quality of life and referral of the retinoblastoma survivors.

Discharge and infection in retinoblastoma post-enucleation sockets.

PURPOSE: To investigate the causes and treatment options for socket discharge and infection in patients enucleated for retinoblastoma (Rb). METHODS: A questionnaire was filled out by (parents of) ocular prosthesis-wearing patients with a history of enucleation as treatment for Rb. We collected data on patients' characteristics, cleaning habits of the prosthesis, frequency of socket irritation, discharge, and infection, and use of antibiotics. With ordinal logistic regression analysis, factors related to the outcome parameters (frequency of irritation, mucoid and purulent discharge) were identified. In a subset of young asymptomatic and symptomatic patients, a swab culture of the socket was performed to determine the presence of microorganisms. RESULTS: A total of 186 patients or their parents (mean age of the patients: 17.3 years, ranging from 0.8 to 88.3 years) filled out the questionnaire. Irritation, mucoid discharge, and purulent discharge were frequently (once a month or more often) experienced in 75 (39.5%), 127 (66.8%), and 15 (13.2%) sockets, respectively. Younger age was associated with a higher frequency of mucoid and purulent discharge. Radiation therapy, chemotherapy, gender, age at surgery, cleaning frequency, and nocturnal wear were not associated with the outcome parameters. In a subgroup of 26 patients, the sockets were swabbed and cultured. All symptomatic patients had a positive bacterial culture versus 15% (2/13) of the asymptomatic patients (P<0.001). Common cold was correlated with both symptoms and presence of bacteria. Haemophilus influenzae and Staphylococcus aureus were the species most frequently cultured. CONCLUSION: Ocular prosthesis-wearing patients often experienced mucoid discharge, and less often irritation and socket infection. These complaints were found to decrease with increasing age, but did not seem to be influenced by cleaning or wearing habits. Symptomatic sockets, with and without discharge, were correlated with the presence of pathogenic bacteria for which local antibiotic treatment seemed effective in most cases.

Orbital implants in retinoblastoma patients: 23 years of experience and a review of the literature.

PURPOSE: To evaluate complications of different types of orbital implants following enucleation for retinoblastoma. METHODS: We performed a retrospective chart study of all patients that underwent enucleation as treatment of retinoblastoma between April 1991 and June 2013. Events of implant exposure, extrusion (defined as a complete loss of the implant, or a major exposure that could not be closed) and socket abnormalities were analysed for association with implant type and influence of additional external beam radiation therapy (EBRT) and/or chemotherapy. RESULTS: A total of 224 enucleations in 216 patients (eight bilateral) were identified. Mean age at surgery was 1.9 (median 1.5) years. Of the 219 included enucleated eyes, 20 were not replaced by a primary implant and 18 were replaced by an Allen implant. Scleral wrapped hydroxyapatite (HA) and acrylic implants (polymethylmethacrylate) were inserted in, respectively, 79 and 102 cases. In the total population, 29 treatment or implant-specific events (13.2%) were registered. Main complications were implant exposure n = 10 (4.6%) and extrusion n = 6 (2.7%). The acrylic/sclera group had less exposures or extrusions (5 of 102, 4.9%) compared to the HA/sclera group (10 of 79, 12.7%), although this difference did not quite reach statistical significance (p = 0.06). Additional treatment (chemotherapy and/or EBRT for the fellow eye) was administered in 78 cases (35.8%). The overall complication rate in the entire study population was significantly higher (16.7% versus 5.7%) in the group exposed to additional therapy (OR 3.3; 95% CI 1.30-8.36 p = 0.008). This negative effect of additional therapy was also significant in the combined acrylic/HA group (OR 2.9; 95% CI 0.97-8.46 p = 0.048). CONCLUSION: Our results suggest a favourable outcome for acrylic implants compared to the HA implant. Additional treatment with chemotherapy and/or EBRT is associated with an increased risk of complications.

Worldwide enucleation techniques and materials for treatment of retinoblastoma: an international survey.

PURPOSE: To investigate the current practice of enucleation with or without orbital implant for retinoblastoma in countries across the world. METHODS: A digital survey identifying operation techniques and material used for orbital implants after enucleation in patients with retinoblastoma. RESULTS: We received a response of 58 surgeons in 32 different countries. A primary artificial implant is routinely inserted by 42 (72.4%) surgeons. Ten (17.2%) surgeons leave the socket empty, three (5.2%) decide per case. Other surgeons insert a dermis fat graft as a standard primary implant (n=1), or fill the socket in a standard secondary procedure (n=2; one uses dermis fat grafts and one artificial implants). The choice for porous implants was more frequent than for non-porous implants: 27 (58.7%) and 15 (32.6%), respectively. Both porous and non-porous implant types are used by 4 (8.7%) surgeons. Twenty-five surgeons (54.3%) insert bare implants, 11 (23.9%) use separate wrappings, eight (17.4%) use implants with prefab wrapping and two insert implants with and without wrapping depending on type of implant. Attachment of the muscles to the wrapping or implant (at various locations) is done by 31 (53.4%) surgeons. Eleven (19.0%) use a myoconjunctival technique, nine (15.5%) suture the muscles to each other and seven (12.1%) do not reattach the muscles. Measures to improve volume are implant exchange at an older age (n=4), the use of Restylane SQ (n=1) and osmotic expanders (n=1). Pegging is done by two surgeons. CONCLUSION: No (worldwide) consensus exists about the use of material and techniques for enucleation for the treatment of retinoblastoma. Considerations for the use of different techniques are discussed.

High resolution SNP array profiling identifies variability in retinoblastoma genome stability.

Both hereditary and nonhereditary retinoblastoma (Rb) are commonly initiated by loss of both copies of the retinoblastoma tumor suppressor gene (RB1), while additional genomic changes are required for tumor initiation and progression. Our aim was to determine whether there is genomic heterogeneity between different clinical Rb subtypes. Therefore, 21 Rb tumors from 11 hereditary patients and 10 nonhereditary Rb patients were analyzed using high-resolution single nucleotide polymorphism (SNP) arrays and gene losses and gains were validated with Multiplex Ligation-dependent Probe Amplification. In these tumors only a few focal aberrations were detected. The most frequent was a focal gain on chromosome 2p24.3, the minimal region of gain encompassing the oncogene MYCN. The genes BAZ1A, OTX2, FUT8, and AKT1 were detected in four focal regions on chromosome 14 in one nonhereditary Rb. There was a large difference in number of copy number aberrations between tumors. A subset of nonhereditary Rbs turned out to be the most genomic unstable, while especially very young patients with hereditary Rb display stable genomes. Established Rb copy number aberrations, including gain of chromosome arm 1q and loss of chromosome arm 16q, turned out to be preferentially associated with the nonhereditary Rbs with later age of diagnosis. In contrast, copy number neutral loss of heterozygosity was detected mainly on chromosome 13, where RB1 resides, irrespective of hereditary status or age. Focal amplifications and deletions and copy number neutral loss of heterozygosity besides chromosome 13 appear to be rare events in retinoblastoma.

[A boy with leukocoria]. / Een jongen met een witte pupil.

A 1.5-year-old boy was referred to the Dutch Retinoblastoma Center with leukocoria, a white pupillary reflex. Fundoscopy revealed a white retinal tumor and ultrasonography showed a calcified mass. The patient underwent enucleation of the left eye. Histopathological examination of the retinal tumor confirmed the diagnosis 'retinoblastoma'. Leukocoria is a cardinal sign of retinoblastoma.